Faculty Bibliography

BACKGROUND:Former American football players are at risk for chronic traumatic encephalopathy (CTE) which may have parkinsonism as a clinical feature. OBJECTIVE:Former football players were prospectively assessed for parkinsonism. METHODS:120 former professional football players, 58 former college football players, and 60 same-age asymptomatic men without repetitive head impacts, 45-74 years, were studied using the MDS-UPDRS to assess for parkinsonism, and the Timed Up and Go (TUG). Traumatic encephalopathy syndrome (TES), the clinical syndrome of CTE, was adjudicated and includes parkinsonism diagnosis. Fisher's Exact Test compared groups on parkinsonism due to small cell sizes; analysis of covariance or linear regressions controlling for age and body mass index were used otherwise. RESULTS:Twenty-two (12.4%) football players (13.3% professional, 10.3% college) met parkinsonism criteria compared with two (3.3%) in the unexposed group. Parkinsonism was higher in professional (p = 0.037) but not college players (p = 0.16). There were no differences on the MDS-UPDRS Part III total scores. Scores on the individual MDS-UPDRS items were low. TUG times were longer in former professional but not college players compared with unexposed men (13.09 versus 11.35 s, p < 0.01). There were no associations between years of football, age of first exposure, position or level of play on motor outcomes. TES status was not associated with motor outcomes. CONCLUSIONS:Parkinsonism rates in this sample of football players was low and highest in the professional football players. The association between football and parkinsonism is inconclusive and depends on factors related to sample selection, comparison groups, and exposure characteristics.

RATIONALE/BACKGROUND:The International Classification of Cognitive Disorders in Epilepsy (IC-CoDE) was recently introduced as a consensus-based, empirically-driven taxonomy of cognitive disorders in epilepsy and has been effectively applied to patients with temporal lobe epilepsy (TLE). The purpose of this study was to apply the IC-CoDE to patients with frontal lobe epilepsy (FLE) using national multicenter data. METHODS:Neuropsychological data of 455 patients with FLE aged 16 years or older were available across four US-based sites. First, we examined test-specific impairment rates across sites using two impairment thresholds (1.0 and 1.5 standard deviations below the normative mean). Following the proposed IC-CoDE guidelines, patterns of domain impairment were determined based on commonly used tests within five cognitive domains (language, memory, executive functioning, attention/processing speed, and visuospatial ability) to construct phenotypes. Impairment rates and distributions across phenotypes were then compared with those found in patients with TLE for which the IC-CoDE classification was initially validated. RESULTS:The highest rates of impairment were found among tests of naming, verbal fluency, speeded sequencing and set-shifting, and complex figure copy. The following IC-CoDE phenotype distributions were observed using the two different threshold cutoffs: 23-40% cognitively intact, 24-29% single domain impairment, 13-20% bi-domain impairment, and 18-33% generalized impairment. Language was the most common single domain impairment (68% for both thresholds) followed by attention and processing speed (15-18%). Overall, patients with FLE reported higher rates of cognitive impairment compared with patients with TLE. CONCLUSIONS:These results demonstrate the applicability of the IC-CoDE to epilepsy syndromes outside of TLE. Findings indicated generally stable and reproducible phenotypes across multiple epilepsy centers in the U.S. with diverse sample characteristics and varied neuropsychological test batteries. Findings also highlight opportunities for further refinement of the IC-CoDE guidelines as the application expands.

INTRODUCTION/BACKGROUND:The presentation, risk factors, and etiologies of white matter hyperintensities (WMH) in people exposed to repetitive head impacts are unknown. We examined the burden and distribution of WMH, and their association with years of play, age of first exposure, and clinical function in former American football players. METHODS:A total of 149 former football players and 53 asymptomatic unexposed participants (all men, 45-74 years) completed fluid-attenuated inversion recovery magnetic resonance imaging, neuropsychological testing, and self-report neuropsychiatric measures. Lesion Segmentation Toolbox estimated WMH. Analyses were performed in the total sample and stratified by age 60. RESULTS:In older but not younger participants, former football players had greater total, frontal, temporal, and parietal log-WMH compared to asymptomatic unexposed men. In older but not younger former football players, greater log-WMH was associated with younger age of first exposure to football and worse executive function. DISCUSSION/CONCLUSIONS:In older former football players, WMH may have unique presentations, risk factors, and etiologies. HIGHLIGHTS/CONCLUSIONS:Older but not younger former football players had greater total, frontal, temporal, and parietal lobe white matter hyperintensities (WMH) compared to same-age asymptomatic unexposed men. Younger age of first exposure to football was associated with greater WMH in older but not younger former American football players. In former football players, greater WMH was associated with worse executive function and verbal memory.

OBJECTIVE:This study was undertaken to evaluate the cross-cultural application of the International Classification of Cognitive Disorders in Epilepsy (IC-CoDE) to a cohort of Spanish-speaking patients with temporal lobe epilepsy (TLE) living in the United States. METHODS:Eighty-four Spanish-speaking patients with TLE completed neuropsychological measures of memory, language, executive function, visuospatial functioning, and attention/processing speed as part of the Neuropsychological Screening Battery for Hispanics. The contribution of demographic and clinical variables to cognitive performance was evaluated. A sensitivity analysis was conducted by examining the base rates of impairment across several impairment thresholds. The IC-CoDE taxonomy was then applied, and the base rate of cognitive phenotypes for each cutoff was calculated. The distribution of phenotypes was compared to the published IC-CoDE taxonomy data, which utilized a large, multicenter cohort of English-speaking patients with TLE. RESULTS:Across the different impairment cutoffs, memory was the most impaired cognitive domain, with impairments in list learning ranging from 50% to 78%. Application of the IC-CoDE taxonomy utilizing a -1.5-SD cutoff revealed an intact cognitive profile in 47.6% of patients, single-domain impairment in 23.8% of patients, bidomain impairment in 14.3% of patients, and generalized impairment in 14.3% of the sample. This distribution was comparable to the phenotype distribution observed in the IC-CoDE validation sample. SIGNIFICANCE/CONCLUSIONS:We demonstrate a similar pattern and distribution of cognitive phenotypes in a Spanish-speaking epilepsy cohort compared to an English-speaking sample. This suggests stability in the underlying phenotypes associated with TLE and applicability of the IC-CoDE for guiding cognitive diagnostics in epilepsy research that can be applied to culturally and linguistically diverse samples.

OBJECTIVE:and to assess the ability of the IC-CoDE to produce definable and stable cognitive phenotypes in a large, multi-center temporal lobe epilepsy (TLE) patient sample. METHOD/METHODS:were derived across samples using the IC-CoDE and compared to distributions of phenotypes reported in existing studies. RESULTS:Impairment rates were highest on tests of language, followed by memory, executive functioning, attention/processing speed, and visuospatial ability. Application of the IC-CoDE using varying operational definitions of impairment (≤ 1.0 and ≤ 1.5 SD) produced cognitive phenotypes with the following distribution: cognitively intact (30%-50%), single-domain (26%-29%), bi-domain (14%-19%), and generalized (10%-22%) impairment. Application of the ≤ 1.5 cutoff produced a distribution of phenotypes that was consistent across cohorts and approximated the distribution produced using data-driven approaches in prior studies. CONCLUSIONS:The IC-CoDE is the first iteration of a classification system for harmonizing cognitive diagnostics in epilepsy research that can be applied across neuropsychological tests and TLE cohorts. This proof-of-principle study in TLE offers a promising path for enhancing research collaborations globally and accelerating scientific discoveries in epilepsy. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

BACKGROUND:Patterns of cognitive impairment in former American football players are uncertain because objective neuropsychological data are lacking. This study characterized the neuropsychological test performance of former college and professional football players. METHODS:One hundred seventy male former football players (n=111 professional, n=59 college; 45-74 years) completed a neuropsychological test battery. Raw scores were converted to T-scores using age, sex, and education-adjusted normative data. A T-score ≤ 35 defined impairment. A domain was impaired if 2+ scores fell in the impaired range except for the language and visuospatial domains due to the limited number of tests. RESULTS:Most football players had subjective cognitive concerns. On testing, rates of impairments were greatest for memory (21.2% two tests impaired), especially for recall of unstructured (44.7%) versus structured verbal stimuli (18.8%); 51.8% had one test impaired. 7.1% evidenced impaired executive functions; however, 20.6% had impaired Trail Making Test B. 12.1% evidenced impairments in the attention, visual scanning, and psychomotor speed domain with frequent impairments on Trail Making Test A (18.8%). Other common impairments were on measures of language (i.e., Multilingual Naming Test [21.2%], Animal Fluency [17.1%]) and working memory (Number Span Backward [14.7%]). Impairments on our tasks of visuospatial functions were infrequent. CONCLUSIONS:In this sample of former football players (most of whom had subjective cognitive concerns), there were diffuse impairments on neuropsychological testing with verbal memory being the most frequently impaired domain.

Due to shared hippocampal dysfunction, patients with Alzheimer's dementia and late-onset epilepsy (LOE) report memory decline. Multiple studies have described the epidemiological, pathological, neurophysiological, and behavioral overlap between Alzheimer's Disease and LOE, implying a bi-directional relationship. We describe the neurobiological decline occurring at different spatial in AD and LOE patients, which may explain why their phenotypes overlap and differ. We provide suggestions for clinical recognition of dual presentation and novel approaches for behavioral testing that reflect an "inside-out," or biologically-based approach to testing memory. New memory and language assessments could detect-and treat-memory impairment in AD and LOE at an earlier, actionable stage.

BACKGROUND:Multiple sclerosis (MS) affects over 2.5 million individuals worldwide, yet much of the disease course is unknown. Hemispheric vulnerability in MS may elucidate part of this process but has not yet been studied. The current study assessed neuropsychological functioning as it relates to hemispheric vulnerability in MS. METHODS:Verbal IQ, as measured by verbal comprehension index (VCI), nonverbal IQ, as measured by perceptual reasoning index (PRI) and memory acquisition were compared in right-handed (dextral) and non-right-handed (non-dextral) persons with MS (PwMS). RESULTS:Linear mixed-effects modeling indicated a significant main effect of handedness, F(1, 195.35) = 3.95, p = .048, for a composite measure of VCI, PRI, and memory acquisition, with better performance for dextral PwMS. In examining differences for specific neuropsychological measures, the largest effect size between dextral and non-dextral participants was seen in PRI (d = 0.643), F(1,341) = 12.163, p = .001. No significant interaction effect between handedness and IQ was found, F(3, 525.60) = 0.75, p = .523. CONCLUSIONS:Dextral PwMS perform better than non-dextral PwMS when assessing neuropsychological performance for memory and IQ combined. Results are suggestive of increased vulnerability in the left brain to the pathological process of MS.

OBJECTIVE:Neuropsychological profiles are heterogeneous both across and within epilepsy syndromes, but especially in frontal lobe epilepsy (FLE), which has complex semiology and epileptogenicity. This study aimed to characterize the cognitive heterogeneity within FLE by identifying cognitive phenotypes and determining their demographic and clinical characteristics. METHOD/METHODS:One hundred and six patients (age 16-66; 44% female) with FLE completed comprehensive neuropsychological testing, including measures within five cognitive domains: language, attention, executive function, processing speed, and verbal/visual learning. Patients were categorized into one of four phenotypes based on the number of impaired domains. Patterns of domain impairment and clinical and demographic characteristics were examined across phenotypes. RESULTS:Twenty-five percent of patients met criteria for the Generalized Phenotype (impairment in at least four domains), 20% met criteria for the Tri-Domain Phenotype (impairment in three domains), 36% met criteria for the Domain-Specific Phenotype (impairment in one or two domains), and 19% met criteria for the Intact Phenotype (no impairment). Language was the most common domain-specific impairment, followed by attention, executive function, and processing speed. In contrast, learning was the least impacted cognitive domain. The Generalized Phenotype had fewer years of education compared to the Intact Phenotype, but otherwise, there was no differentiation between phenotypes in demographic and clinical variables. However, qualitative analysis suggested that the Generalized and Tri-Domain Phenotypes had a more widespread area of epileptogenicity, whereas the Intact Phenotype most frequently had seizures limited to the lateral frontal region. SIGNIFICANCE/CONCLUSIONS:This study identified four cognitive phenotypes in FLE that were largely indistinguishable in clinical and demographic features, aside from education and extent of epileptogenic zone. These findings enhance our appreciation of the cognitive heterogeneity within FLE and provide additional support for the development and use of cognitive taxonomies in epilepsy.